LV12559B - Derivatives of 1,3,4-oxadiazolone - Google Patents

Abstract

The present invention provides novel oxadiazolone derivatives having general formula (I), wherein A, B, D and R are as defined herein, or a nontoxic pharmaceutically acceptable salt or solvate thereof and are useful in the treatment of disorders which are responsive to the opening of the large conductance calcium-activated potassium channels.

Description

-1 - -1 - LV 12559

DERIVATIVES OF 1,3,4-OXADIAZOLONE 5

RELD QF THE INVENTION 10 The present invention is directed to novel derivatives of a 1,3,4- oxadiazol-2(3H)-one compound which is a modulator of the large-conductance calcium-activated potassium (BK) channels and, therefore, useful in the protection of neuronal celis and diseases arising from dysfunction of celluiar membrane polarization and conductance. The 15 present invention also provides a method of treatment with the novel substituted oxadiazolone derivatives and to pharmaceutical compositions thereof.

20 BACKGROUND OF THE INVENTION

Stroke is presently recognized as the third ieading cause of adult disability and death in the United States and Europe. In the past decade, several therapeutic approaches for the minimization of stroke-related 25 brain damage have been pursued including inhibitors of AMPA/kainate, N-methyl-D-aspartate (NMDA) and adenosine reuptake inhibitors. It is the object of the present invention to provide novel compounds that wiil modulate potassium channels, in particular, large-conductance calcium-activated potassium (BK) channels vvhich will be useful in reducing 30 neuronal damage during ischemic conditions of a stroke episode. -2-

Potassium channels play a key role in regulation of celi membrane potential and modulation of celi excitability. Potassium channels are themselves regulated by voltage, celi metabolism, calcium ion and receptor mediated processes. [Cook, N.S., Trends in Pharmacol. 5 Sciences. 9, pp. 21-28 (1988); and Quast, U. and Cook, N.S., Trends in Pharmacol. Sciences. 10, pp. 431-435 (1989)]. Calcium-activated potassium (Kq3) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of Kq3 channels is regulated by intracellular [Ca2+], membrane potential and 10 phosphorylation. On the basis of their single-channel conductances in symmetrical K+ Solutions, Kca channels are divided into three subclasses: large conductance (BK) >150 pS; intermediate conductance 50-150 pS; small conductance < 50 pS. ("pS" stands for picosiemen, a unit of electrical conductance.) Large-conductance calcium-activated potassium 15 (BK) channels are present in many excitable celis including neurons, cardiac celis and various types of smooth muscle celis. [Singer, J. J. and VValsh, J. V., Pflūoers Archiv.. 408. pp. 98-111 (1987); Baro, I., and Escande, D., Pflūoers Archiv.. 414 (Suppl. 1), pp. S168-S170 (1989); and Ahmed, F. et aļ., Br. J. Pharmacol.· 83. pp. 227-233 (1984)]. 20

Potassium ions piay a dominant role in controliing the resting membrane potential in most excitable celis and in maintaining the transmembrane voltage near the K+ equilibrium potential (EļJ of about -90 mV. It has been shown that opening of potassium channels shifts the celi 25 membrane potential tovvards the equilibrium potassium membrane potential (Ek), resulting in hyperpolarization of the celi. [Cook, N.S., Trends in Pharmacol. Sciences. £, pp. 21-28 (1988]. Hyperpolarized celis show a reduced response to potentially damaging depolarizing stimuli. BK channels vvhich are regulated by both voltage and intracellular Ca2+ 30 act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore celi hyperpolarization -3- LV 12559 via opening of BK channels may result in protection of neuronal celis under ischemic conditions.

The role of potassium channels in the operation of the smooth 5 muscle of the human urinary bladder is discussed by S. Trivedi, et ai. in Biochemical and Biophvsical Research Communications· (1995), 213. No.2, pp. 404-409.

A range of synthetic and naturally occurring compounds with BK 10 opening activity have been reported. The avena pyrone extracted from avena sativa-common oats has been identified as a BK channel opener using a lipid bi-layer technique [International Patent application WO 93/08800, published May 13,1993]. The flavanoid, Phloretin has been found to affect the opening of Ca2+-activated potassium channels in 15 myelinated nerve fibers of Xenopus laevis using outside-out patchec [Koh, D-S., sili·. Neuroscience Lett.. 165. pp. 167-170 (1994)]. U.S. 3,971,803 issued to S. Rosenberger and K. Schvvarzenbach on July 27,1976, relates to compounds of Formula (i): 20

n—n— ch2

oh y—c-2 r3 r2 vvherein Rļ is alkyl, cycloalkyl or aralkyl; 25 R2 is hydrogen or R-ļ; R3 is hydrogen or alkyl; Y and 2 are independently O or S; -4- R4 is either (1), if m=1, C-ļ.8 alkylene, -ΟχΗ^Ό-ΟγΙ^γ- (Q is 0 or S, x and y are integers whose sum is 2 to 4), phenylene, diphenylene or

— N— CH2^QV- OH naphthalene or a —o'' j /—( group; y—c=z r3 r2 or (2) if m=2, alkylene, alkylene ether, alkyiene thioether, diphenylene, or 5 napthalene. The compounds are antioxidants for organic polymers. EPO 0-533276-A1 published on March 24,1993, shows compounds of Formula (ii): o

II

N^C>0

I_I N-C, 10 vvherein one of P or Q is an ortho-substituted phenyl group and the other a substituted benzyl. The Formula (ii) compounds are miticides and insecticides. A.E.VVilder Smith disclosed in Arzneim. Forsch. (1967) £7, No. 17, pp. 768-772, the preparation and study of compounds of Formula (iii):

OH

vvherein X is H or Cl and n is 1 or 2. The compounds have tuberculostatic properties. Formula (iii) compounds do not encompass substitution para to the hydroxyl group. 20 -5- LV 12559 J. L. Romine, et al. in International Patent Application WO 98/04135, published February 5,1998, describe a series of diphenyl heterocycles of the Formula (iv): 5

R' (iv) wherein Het is a heterocyclic molety selected from inter alia. oxadiazolone. The compounds are useful as modulators of the large conductance calcium-activated potassium channels and the starting 10 material for the preparation of the compounds of the present invention is described therein vvherein Het is 1,3,4-oxadiazol-2(3H)-one, m = 1 and n = 0, Rc is chloro, Rd is trifluoromethyl and Ra = Rb = Re is hydrogen.

None of these references teach or suggest the novel compounds of 15 the present invention.

SUMMARY OF THE INVENTION 20 The present invention provides novel derivatives of 1,3,4- oxadiazolone having the general formula

-6- vvherein A, B, 0 and R are as defined below, or a nontoxic pharmaceutically acceptable salt or solvate thereof. The present invention also provides pharmaceutical compositions comprising said derivatives and to the method of treatment of disorders sensitive to 5 potassium channel opening activity such as ischemia, stroke, convulsions, epiiepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, splnal cord injury, sexual dysfunction, and urinary incontinence.

10 DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel derivatives of 3-[(5-chloro-2-hydroxyphenyl)methylļ-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)· one which is a potent opener of the large conductance, calcium-activated 15 K+-channels (BK channel) and the novel derivatives have the general Formula

20 vvherein A B D n 25 R is a direct bond or -CH2O-; is a direct bond or oxygen; is -(CH^n- or -CH£HOHCH2-; is an integer from 1 to 4; Θ Θ Θ is —NR1R2or —NR1R2R3X invvhich X is a counter anion; and -7- -7- LV 12559 R1.R2, and R3 each are independently hydrogen or C-1.4 alkyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof. 5 The present invention also provides a method for the treatment of or protection from disorders whlch are mediated by opening of the large conductance calcium-activated K+ channels (BK channels) in a mammai in need thereof, which comprises administering to said mammai a therapeutically effective amount of a compound of Formula J or a nontoxic 10 pharmaceutically acceptable salt thereof. Preferably, the compounds of Formula l are useful in the treatment of ischemia, stroke, epilepsy, convulsions, asthma, imtable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction, and urinary incontlnence and other disorders sensitive to BK channel activating activity. 15

The term “Ci_4 alkyl” as used herein and in the claims (uniess the context indicates othervvise) means straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl. Preferably, these groups contain from 1 to 2 carbon atoms. 20

The term "a nontoxic pharmaceutically acceptable salt" and “counter anion” as used herein and in the claims is intended to inciude nontoxic acid addition salts and counter anions with inorganic and organic acids. Suitable salts with an acid and/or suitable counter anions of an 25 acid are intended to inciude inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and the like, and organic acid salts and/or counter anions of an acid such as formate, acetate, maleate, citrate, succinate, ascorbate, lactate, fumarate, methanesulfonate and tartrate which have been used to form salts of 30 basie amines and quatemary amines. -8-

As the compounds of the present invention may possess an asymmetric carbon atom, the present invention is intended to include the racemate as well as the individual enantiometric forms of the compounds of Formula I as described herein and in the claims, e.g., the (D), (L) and 5 (DL) forms of norcamitine and camitine.

Generally, pharmaceutically acceptable salts of the invention are those in vvhich the counter anion does not contribute significantly to the toxicity or pharmacological activity of the salt. In some instances, they 10 have physical properties which make them more desirable for pharmaceutical formulations, such as solubility, lack of hygroscopicity, compressibility vvith respect to tablet formation and compatibility with other ingredients with vvhich the substance may be used for pharmaceutical purposes. The salts are routinely made by admbdure of a Formula I 15 compound with the selected acid, preferably by contact in solution employing an excess of commonly used inert solvents such as vvater, ether, dioxane, methylene chloride, isopropanol, methanol, ethanol, ethyl acetate and acetonitrile. They may also be made by metathesis or treatment with an ion exchange resin under conditions in vvhich the 20 appropriate ion of a salt of the substance of the Formula I is replaced by another ion under conditions vvhich allovv for separation of the desired species such as by precipitation from solution or extraction into a solvent, or elution from or retention on an ion exchange resin. 25 Certain compounds of the present invention including the pharmaceutically acceptable salts thereof can exist as solvated forms including hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. The products may be true solvates, vvhile in other cases, the products may merely retain adventitious solvent 30 or be a mixture of solvate plus some adventitious solvent. It should be appreciated by those skilled in the art that solvated forms are eguivalent -9- -9- LV 12559 to unsolvated forms and are intended to be encompassed vvithin the scope of the present invention.

In the method of the present invention, the term "therapeutica!!y 5 effective amounf means the total amount of each active component of the composition that is sufficient to show a meaningful patient benefit, i.e., healing of acute conditions characterized by openers of large conductance calcium-activated K+ channels or increase in the rāte of healing of such conditions. When applied to an individual active 10 ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The terms “treat, treating, treatment" as used herein and in the claims means preventing or 15 ameliorating diseases, tissue damage and/or symptoms associated with dysfunction of cellular membrane polarization and conductance.

In another aspect, this invention provides vvater-soluble prodrugs of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyi]-1,3,4-20 oxadiazol-2(3/-/)-one vvhich is described in WO 98/04135. As used herein the term prodrug denotes a derivative of an active drug vvhich is converted after administration back to the active drug. More particularly, it refers to derivatives of 1,3,4-oxadiazol-2(3H)-one compounds which may be active drugs and/or vvhich are capable of undergoing hydrolysis of the ester or 25 methyleneoxy ester moiety or cleavage of the ester so as to release active free drug. The physiologically hydrolyzable groups serve as prodrugs by being hydrolyzed in the body to yield the parent drug per se, and thus, the vvater-soluble prodrugs of the present invention are preferred for administration of the parent drug.

In stili another aspect, this invention provides a method for the treatment of or protection from disorders vvhich are mediated by opening 30 -10- of the large conductance calcium-activated K+ channels (BK channels) in a mammai in need thereof, which comprises administering to said mammai a therapeutically effective amount of a compound of Formula I or a nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof. 5 Preferably, the compounds of Formula I are useful in the treatment of ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, urinary incontinence and sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, 10 psychogenic etiology or any other cause) and women by improving blood flow to the genitalia, especially the corpus cavemosum, and other disorders sensitive to BK channel activating activity. Most preferably, the compounds of Formula I are useful in the treatment of cerebral ischemia/stroke. 15

In stili yet another aspect, this invention provides pharmaceutical compositions comprising at least one compound of Formula l in combination with a pharmaceutical adjuvant, carrier or diluent. 20 The compounds of Formula I may be prepared by various procedures such as those illustrated herein in the examples, in the Reaction Schemes and variations thereof which would be evident to those skilled in the art. The various prodrug compounds of Formula I may advantageously be prepared from the active drug substance of Formula II 25 which is itself prepared by the general procedure described in WO 98/04135 and in Example I and used as the starting material in the methods illustrated in Reaction Schemes 1 to 5. -11 - -11 - LV 12559 REACTION SCHEME 1

II III

5

The preparation of 1,3,4-oxadiazol-2-(3H)-one derivatives of Formula V is illustrated in Reaction Scheme 1. The compound of Formula II is treated with phosgene and a catalytic amount of a phase transfer reaģent such as benzyltriphenyl phosphonium chloride in toluene 10 and heated in a sealed tube to provide the chloroformate of Formula III which is then treated with an appropriateiy substituted N,N-dialkylaminoalcohol in an inert organic solvent such as methylene chloride to producē the carbonate compounds of Formula IV. When it is desired to prepare the compounds of Formula V, the amino compound of Formula IV 15 is quatemarized with a methyiating aģent such as methyl methanesulfonate to producē the quatemary amine of Formula V by Standard procedures well-known to those skilled in the art. -12- REACTION SHEME 2 -12-

NR1R2 VIII a-c 5

When it is desired to preparē compounds of Formula VIII vvherein n is 1 to 4, the compound of Formula II is deprotonated with a base such as sodium hydride and then acylated with the desired N,N-dialkylamino acid chioride to producē the ester of Formula VII which is advantageously 10 quatemarized with an alkylating aģent such as methyl methanesulfonate to afford the quatemary amine of Formula VIII. -13- -13- LV 12559 REACTION SCHEME 3

II IX

XI xii 5

The preparation of compounds of the Formula XII is illustrated in Reactlon Scheme 3 vvherein R1, R2, R3 and n are as defined herein. The compound of Formula II is deprotonated with a base such as sodium hydride and then alkylated with chloromethyl methyl sulfide to provide the 10 thiomethylmethyl ether of Formula IX. Treatment of the compound of Formula IX with a chlorinating aģent such as sulfuryl chloride yields the chloromethyl ether of Formula X which is then treated with the desired -14- N,N-dialkylaminoacid in the presence of a base such as cesium carbonate to afford the corresponding methoxy ester of Formula XI. When it is desired to prepare the compounds of Formula XII, the amine of Formula XI is quatemarized with a methylating aģent such as methyl 5 methanesulfonate to producē the quatemary amine of Formula XII. REACTION SCHEME 4

X

10 XIII

The preparation of the compound of Formula XIII is readiiy carried out by treating the chloromethyl ether of Formula X with camitine in the 15 presence of a base such as cesium carbonate and then treating the subsequent product with a methylating aģent such as methyl methanesulfonate to afford the quatemary amine of Formula XIII. -15- LV 12559 REACTION SCHEME 5

5 -16-

The preparation of compounds of the Formula XVII is illustrated in Reaction Scheme 5 vvherein R1, R2, R3 and n are as defined herein. The compound of Formula II is deprotonated with a base such as sodium hydride and then alkylated with iodomethyl butyl carbononothioate to give 5 the methoxythiocarbonate of Formula XIV. Treatment of the intermediate of Formula XIV with a chlorinating aģent such as sulfuryl chloride producēs the chloroformate of Formula XV, vvhich is then treated with the desired N,N-dialkylamino alcohol to give the corresponding methoxy carbonate of Formula XVI. The compounds of Formula XVI may 10 subsequently be alkylated with a methylating aģent such as methyl methanesulfonate to afford the quatemary amine of Formula XVII.

In a preferred embodiment of the invention the compounds of Formula I have the Formula la 15

vvherein A is a direct bond or -CH20-; B is a direct bond or oxygen; D is -(CH^n- or -CH£HOHCH2- vvherein n is 1 to 4; and R1 and R2 are 20 hydrogen or Ci.4alkyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof. More preferably, A is a direct bond or -CH20-; B is a direct bond; D is -(CH^n- vvherein n is 1,2 or 3; and R1 and R2 are methyl or ethyl. It is most preferred that A is -CH20-; B is a direct bond; D is -{CH^r,- vvherein n is 2 or 3; and R1 and R2 are methyl; or a nontoxic 25 pharmaceutically acceptable salt or solvate thereof. -17- -17- LV 12559 ln another preferred embodiment of the invention the compounds of Formula I have the Formula Ib

5 vvherein A is a direct bond or -CH20-; B is a dlrect bond or oxygen; D is -(CH^n- or -CH£HOHCH2- wherein n is 1 to 4; R1,R2 and R3 are Θ hydrogen or Ci^alkyl; and X is a counter anion or a nontoxic pharmaceutically acceptable salt or solvate thereof. More preferably, A is 10 a direct bond or -CH20-; B is a direct bond; D is -(CH^n- wherein n is 1,2 Θ

or 3; R1 ,R2 and R3 are methyl; and X is chloro, bromo, suifate, phosphate or methanesulfonate. It is most preferred that A is -CH20-; B is a direct bond; D is -(CH2)n- vvherein n is 3; R1, R2 and R3 are methyl; Θ and X is methanesulfonate; or a nontoxic pharmaceuticaliy acceptable 15 salt or solvate thereof.

In another embodiment, this invention includes pharmaceuticai compositions comprising at least one čompound of Formula I in combination with a pharmaceuticai adjuvant, carrier or diluent. 20

In stili another embodiment, this invention relates to a method of treatment or prevention of disorders responsive to opening of potassium channels in a mammai in need thereof, vvhich comprises administering to said mammai a therapeutically effective amount of a čompound of -18-

Formula I or a nontoxic phamnaceutically acceptable salt, solvate or hydrate thereof.

In yet another embodiment, this invention relates to a method for 5 treating ischemia, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, male and female sexual dysfunction, urinary incontlnence and especially stroke in a mammai in need thereof, vvhich comprises administering to said mammai a therapeutically effective amount of a compound of Formula I or a 10 nontoxic pharmaceutically acceptable salt, solvate or hydrate thereof.

Bioloaical Activitv

Potassium (K+) channels are structurally and functionally diverse 15 families of K+-selective channel proteīns vvhich are ubiquitous in celis, indicating their Central importance in regulating a number of key celi functions [Rudy, B., Neuroscience. 25. pp. 729-749 (1988)]. While widely distributed as a class, K+ channels are differentiaily distributed as individual members of this class or as families. [Gehlert, D.R., et aļ., 20 Neuroscience. 52. pp. 191-205 (1993)]. In general, activation of K+ channels in celis, and particularly in excitable celis such as neurons and muscle celis, leads to hyperpolarization of the celi membrane, or in the case of depolarized celis, to repolarization. in addition to acting as an endogenous membrane voltage clamp, K+ channels can respond to 25 important cellular events such as changes in the intracellular concentration of ATP or the intracellular concentration of calcium (Ca2+). The Central role of K+ channels in regulating numerous celi functions makes them particularly important targets for therapeutic development. [Cook, N.S., Potassium channels: Structure, classification, function and 30 therapeutic potential. Ellis Horvvood, Chinchester (1990)]. One class of K+ channels, the large-conductance Ca2+-activated K+ channels (BK or -19- -19- LV 12559 BK channels), is regulated by transmembrane voltage, intracellular Ca2+, and a variety of other factors such as the phosphorylation stata of the channel protein. [Latorre, R., eisļ., Ann. Rev. Phvsiol.. 51. pp. 385-399 (1989)]. The large, singla channel-conductanca (generally >150 pS) and 5 high degree of specificity for K+ of BK channels indicates that small numbers of channels could profoundly affect membrane conductance and celi excitability. Additionally, the increase in open probability with increasing intracellular Ca2+ indicates involvement of BK channels in the modulation of Ca2+-dependent phenomena such as secretion and 10 muscular contraction. [Asano, M., gt gļ., J. Pharmacol. Exp. Ther.. 267. pp. 1277-1285 (1993)].

Openers of BK channels exert their cellular effects by increasing the open probabi!ity of these channels [McKay, M.C., gt aļ., J. 15 Neurophysiol.. 71. pp.1873-1882 (1994); and Olesen, S.-P., Exp. Qpin. Invest. Druas. pp. 1181-1188 (1994)]. This increase in the opening of individual BK channels collectively results in the hyperpolarization of celi membranes, particuiarly in depolarized celis, produced by significant increases in whole-cell BK-mediated conductance. 20

The ability of the compound of Example 1 to open BK channels and increase whole-cell outvvard (K+) BK-mediated currents was assessed under voltage-clamp conditions by determining their ability to increase cloned mammalian (mSlo or hSlo) BK - mediaied outward current 25 heterologously expressed in Xenopus oocytes [Butler, A., et aĻ. Science. 261. pp. 221-224 (1993); and Dworetzky, S.I., gtgļ., Mol· Brain Res.. 27. pp.189-193 (1994)]. The two BK constructs employed represent nearly structurally identical homologous proteīns, and have proven to be pharmacologica!ly identical in our tests. To isolate BK current from native 30 (background, non-BK) current, the specific and potent BK channel- blocking toxin iberiotoxin (ΙΒΤΧ) [Galvez, A., et aļ., Biol. Chem. 265. pp. -20- 11083-11090 (1990)] was employed at a supramaximal concentration (50 nM). The relative contribution of BK channels current to total outward current was determined by subtraction of the current remaining in the presence of ΙΒΤΧ (non-BK current) from the current profilēs obtained in ali 5 other experimental conditions (control, drug, and wash). It was determined that at the tested concentration the compound profiled did not effect non-BK native currents in the oocytes. The compound of Example 1 was shown in at least 5 oocytes at a concentration of 1μΜ to increase BK current to 126% of control of ΙΒΤΧ-sensitive current. Recordings were 10 accomplished using Standard two-electrode voltage clamp techniques [Stuhmer, W., et ai.. Methods in Enzvmoloov. 207. pp. 319-339 (1992)]; voltage-clamp protocols consisted of 500-750 ms duration step depolarizations from a holding potential of -60 mV to +140 mV in 20 mV steps. The experimental media (modified Barth's solution) consisted of (in 15 mM): NaCI (88), NaHC03 (2.4), KCI (1.0), HEPES (10), MgS04 (0.82), Ca(N03)2 (0.33), CaCI2 (0.41); pH 7.5. A rapid screen to determine the abiiity of prodrugs to hydrolyze and release the drug (compound of Example 1) is conducted as follows. A 1 20 mg/mL stock solution of the prodrug is prepared in distilled water or acetonitriie or PEG-400. Plasma from freshly collected rat or human blood is used in this assay. To 1 mL of plasma at 37° C was added 10 μΙ_ of stock solution of prodrug and mixed gently. Immediately after the mixing, 100 μΙ_ of plasma was removed and quenched with 300 \iL of 25 acetontrile (Zero time sample). Samples were also obtained at 30 minūtes and quenched immediateiy. The quenched samples were centrifuged to obtain a clear supematant for analysis. The stock solution, T=0 and T=30 samples were analyzed by a HPLC assay that separates the drug from the prodrug. Based on the relative peak areas of prodrug 30 and drug in these samples, different prodrugs are characterized as fast, moderate and slow release aģents. For example, in this modei, the -21 - -21 - LV 12559 compound of Bcample 13 was dissolved in PEG-400 at a concentration of 1 mg/mL and incubated at 10 ug/mL in fresh rat plasma at 37°C. Anaiysis of the solution 5 minūtes after incubation indicated conversion of the compound of Example 13 to the compound of Example 1. 5

To determine the ability of the compounds of the present invention to reduce celi loss resulting from neuronal ischemia, a Standard focai cerebral ischemia is induced by permanent occlusion of the left middle cerebral artery (MCA) and common carotid artery (CCA) with one hour 10 occlusion of the right CCA in the Wistar rat. The surgeries are performed using the sub-temporal approach of A. Tamura, et al.. J. Cereb. Blood Flow Metab.. 1, pp. 53-60, (1981) and its modifications [K. Osbome, et al.. J. Neurol Neurosura, Psvchiatrv. 50. pp. 402-410 (1987) and S. Menzies, et al.. Neurosurgerv. 31. pp. 100-107, (1992).] 15

The compound of Example 13 was evaluated in the focai stroke modei involving permanent occlusion of the left MCA (MCAO) and CCA (CCAO) and temporary occlusion of the right CCA in the Wistar rat. This procedure results in a reliably large neocortical infarct volume that is 20 measured by means of vital dye exclusion in serial slices through the brain 24 hours after MCAO. In the present tēst, compounds were administered using an i.v. or i.p. route of administration two hours after occlusion. For example, in this modei the compound of Example 13 significantiy reduced the cortical infarct volume by about 17% when 25 administered intravenously (1 mg/kg) as a single bolus two hours after middle cerebral artery occlusion as compared to vehicle-treated (water) control.

The results of the above in vitro and in vivo tests demonstrate that 30 the novel 1,3,4-oxadiazol-2(3H)-one compounds of the present invention are useful for the treatment of human disorders arising from dysfunction of cellular membrane polarization and conductance and, preferably, are -22- indicated for the treatment of ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord ir»jury, sexual dysfunction, and urinary incontinence and other disorders sensitive to BK channel activating activity. Most preferably, the 5 compounds of Formula I are useful in the treatment of cerebral ischemia/stroke.

The compounds of Formula I or pharmaceutical compositions thereof are useful in the treatment, alleviation or elimination of disorders 10 or other disorders associated with the BK channeis. Such disorders include ischemia, stroke, convulsions, epilepsy, asthma, irritable bovvel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction and urinary incontinence and other disorders sensitive to potassium channel openers. 15

For therapeutic use, the pharmacologically active compounds of Formula I wili normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically 20 acceptable carrier and, optionaily, with pharmaceutically acceptable adjuvants and excipients employing Standard and conventional techniques.

The pharmaceutical compositions include suitable dosage forms for 25 oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or peliet form, or in the form of a troche or iozenge. The solid carrier may contain conventional excipients such as binding aģents, fillers, 30 tableting lubricants, disintegrants, vvetting aģents and the iike. The tablet may, if desired, be film coated by conventional techniques. If a liquid cam'er is employed, the preparation may be in the form of a syrup, -23- -23- LV 12559 emulsion, soft gelatin capsule, steriie vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitutlon with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending aģents, emulsifying 5 aģents, vvetting aģents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring aģents. For parenteral administration, a vehicle normally will comprise steriie water, at ieast in large part, although saline Solutions, glucose Solutions and like may be utilized. Injectable suspensions also may be used, in vvhich case 10 conventional suspending aģents may be employed. Conventional preservatives, buffering aģents and the like also may be added to the parenteral dosage forms. Particulariy useful is the administration of a compound of Formula I directly in parenteral formulations. The pharmaceutical compositions are prepared by conventional techniques 15 appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See, for example, Reminaton's Phanmaceutical Sciences. Mack Publishing Company, Easton, PA, 17th edition, 1985. 20 The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient and mode of administration, but also on the degree of potassium channel activating activity desired and the potency of the particular compound being utilized for the particular disorder of disease 25 concemed. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative Ievel of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per 30 day) is vvithin the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to producē the desired therapeutic effect. -24- A suitable dose of a compound of Formula I or pharmaceutical composition thereof for a mammai, includīng man, suffering from, or likely to suffer from any condition as described herein is an amount of active ingredient from about 0.1 ng/kg to 10 mg/kg body vveight. For parenteral 5 administration, the dose may be in the range of 0.1 ng/kg to 1.0 mg/kg body vveight for intravenous administration. The active ingredient will preferably be administered either continuously or in equal doses from one to four times a day. Hovvever, usually a small dosage is administered, and the dosage is gradually increased until the optimal dosage for the 10 host under treatment is determined.

Hovvever, it vvill be understood that the amount of the compound actually administered vvill be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the choice of 15 compound of be administered, the chosen route of administration, the age, vveight, and response of the individual patient, and the severity of the patienfs symptoms.

The follovving examples are given by way of illustration and are not 20 to be construed as limiting the invention in any way inasmuch as many variations of the invention are possible vvithin the meaning of the invention.

25 DESCRIPTION OF SPEC1F1C EMBODIMENTS

In the follovving examples, ali temperatures are given in degrees Centigrade. Melting points vvere recorded on a Gallenkamp capiilary melting point apparatus temperatures are uncorrected. Proton magnetic 30 resonance (1H NMR) vvas recorded on a Bruker AC 300. Ali spectra vvere determined in the solvents indicated and Chemical shifts are reported in 6 -25- -25- LV 12559 units dovvnfield from the internai Standard tetramethylsiiane (TMS) and interproton coupling constants are reported in Hertz (Hz). Splitting pattems are designated as follovvs: s, singlet; d, doublet; t, tn'plet; q, quartet; m, muitipiet; br, broad peak; dd, doublet of doublet; bd, broad 5 doublet; dt, doublet of triplet; bs, broad singlet; dq, doublet of quartet. Infrared (IR) spectra using potassium bromlde (KBr) were determined on a Perkin Elmer 781 spectrometer from 4000 cm*1 to 400 cm*1, calibrated to 1601 cm*1 absorption of a polystyrene film and reported in reciprocal centimeters (cm*1). Low resolution mass spectra (MS) and the apparent 10 molecular (MH+) or (M-H)* was determined on a Rnnigen TSQ 7000.

High resolution mass spectra was determined on a Kratos MS50 in FAB mode using cesium iodide/glycerol as internai reference. The element analysis are reported as percent by weight. 15 The follovving examples illustrate procedures for the preparation of starting materiāls, intermediates and methods for the preparation of Products according to this invention. It should also be evident to those skīlled in the art that appropriate substitution of both materiāls and methods disclosed herein will producē the examples illustrated below and 20 those encompassed by the scope of this invention. EXAMPLE 1 25 3-rf5-Chloro-2-hvdroxvohenvnmethvn-5-f4-ftrifluoromethvnohenvn-1,3.4-oxad!azol-2(3ffl-one STEP A. 5-Γ4-ΓΓ rifluoromethvODhenvll-l .3.4-oxadiazol-2(3HV-one 30 4-(Trifluoromethyl)benzoic acid hydrazide (commercially available from Maybridge Chemicals) (5 g, 24.5 mmol) was taken up in THF (250 -26- ml) / triethylamine (2.7 ml, 26 mmol) under N2 and 1,1'-carbonyl-diimidazole (4.2 g, 26 mmol) added. The solution was stirred for 18 h ai 24°C, concentrated, and the residue was taken up in ethyl acetate, washed with 1N HCI solution, sat'd NaHC03 solution, and brine prior to 5 drying (MgSO^. Concentration gavē 5 g (89%) of the title compound from vvhich a sample was recrystallized from diethyl ether/hexanes: mp 214-216°C. MS m/z. 231 (MH+). IR (KBr) 3280, 1778,1608,1420, 1318,1170,1114 cm-1; 10 1H NMR (DMSO-d6) δ 7.87 (2H, d, J = 8.3 Hz), 7.96 (2H, d, J = 8.3 Hz), 12.77 (1H, br.s);

Anal. Calcd. for CgH5F3N2O2-064 H20: C, 46.74; H, 2.24; N, 12.11. 15 Found: C, 47.07; H, 2.10; N, 12.34.

Step B. 3-ff5-Chloro-2-methoxvDhenvftmethvn-5-r4-ftrifluoromethvn-phenvll-1.3.4-oxadiazol-2(3H1-one 20 5-[4-(Trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(H)-one (11.75 g, 51 mmol) and 5-chloro-2-methoxybenzylbromide [N. Meanwell, et al., Bioora. Med. Chem. Lett. 6. pp. 1641-1646 (1996)] (12.0 g, 51 mmol) and 11.2 g (81 mmol) of potassium carbonate were added to CH3CN (300ml) under nitrogen and potassium iodide (0.2 g, 1.2 mmol) was added. The solution 25 was refluxed for 16 h, cooled, poured into water (1500 ml) and stirred vigorously. The precipitate was filtered to give a solid vvhich was recrystallized from CH3CN to give 15.2 g (78%) of the title compound. mp 144 - 145°C. MS(ESI)m/z. 385 (MH+). 30 IR (KBr) 3440,1782, 1492, 1324, 1248,1168 cm-1; -27- -27- LV 12559 1H NMR (300 MHz, DMSO) δ 3.79 (3H, s), 4.91 (2H, s), 7.07 (1H, d, J = 8.8 Hz), 7.35-7.38 (2H, m), 7.88 (2H, d, J * 8.4 Hz), 7.96 (2H, d, J = 8.2 Hz); 5 Anal. Calcd. for C17H12CIF3N2O30.1 H20: C, 52.81; H, 3.19; N, 7.25.

Found: C, 53.03; H, 3.20; N, 7.31.

Step C. 3-ri5-Chloro-2-hvdroxvDhenvnmethyll-5-r4-ftrifluoromethvn-phenvn-1.3.4-oxadiazol-2(3H1-one 10 3-[(5-Chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl)-phenyl]-1,3,4-oxadiazol-2(3H)-one (15.2 g, 39.6 mmol) was admixed with pyridine hydrochloride (19.7 g, 0.17 mol) and heated at 225°C for 2 h.

The hei solution was poured into 800 ml of 1 N HCI and the mixture was 15 stirred for 10 min. The solid was collected, vvashed with 1 N HCI and dried at 80°C under vacuum to afford 13.1 g of an off-white solid. Recrystallization from acetonitrile gavē 10.8 g of the title compound as fluffy needles, mp 217-218°C. MS m/z 371 (MH+). 20 IR (KBr) 3354,1762,1500,1324,1068 cm-1; 1H NMR (DMSO-dg) δ4.98 (2H, s), 6.84 (1H, d, J = 8.7 Hz), 7.20 (1H, dd, J = 8.7 Hz, 2.6 Hz), 7.30 (1H, d, J = 2.5 Hz), 7.89 (2H, d, J = 8.6 Hz), 7.97 (1H, d,Js8.6 Hz), 10.11 (1H, br.s); 25

Anal. Calcd. for C16H10CIF3N2O3: C, 51.84; H, 2.72; N, 7.56.

Found: C, 51.88; H, 2.58; N, 7.57. -28- EXAMPLE 2 3-rr5-Chloro-2-rrrr2-fdimethvlamino)ethvnoxvl carbonvll oxvlDhenvnmethviļ-5-r4-ftrifluoromethynphenyn-1.3.4-oxadiazol-5 2(3HVone

Step A. 4-Chloro-2-rr5-f4-ftrifluoromethvflohenvll-2.3-dihvdro-2-oxo-1.3.4-oxadiazol-3-vnmethvl1phenvl chloroformate 10 A stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4- (trifluoromethyl)phenylļ-1,3,4-oxadiazoi-2(3H)-one (1 g, 2.69 mmol) and BnPh3PCI (25 mg) in 1.9 molartoluene solution of phosgene (15 mL) was heated at 120°C ovemight in a sealed tube. After removai of excess phosgene, the toluene solution was rotary evaporated to dryness to afford 15 the chloroformate product as a white semi-solid (1.18 ģ).

Step B. 3-rr5-Chloro-2-rrrr2-(dimethvtamino1ethvnoxvļ carbonvll oxvlphenvnmethvn-5-r4-ftrifluoromethvnphenvn-1.3.4-oxadiazol-2(3H1-one 20

To a stirred cold (0°C) solution of the chloroformate of Step A (0.6 g, 0.15 mmol) in anhydrous CH2Cl2 (5 mL), neat 2-(dimethylamino)-ethanol (0.41 g, 0.45 mmol) was added dropwise. The resultant mixture was allowed to warm to room temperature and maintained for 2-3 hrs. 25 The CH2CI2 was rotary evaporated at room temperature and the residue was partitioned between ether and 5% NaHC03- The ether layer was separated and washed with brine and then dried (MgS04). Evaporation of the solvent gavē the product as a light yellow oil (0.613 g). Reaction of the crude product with anhydrous HCI in ether gavē the corresponding 30 hydrochloride salt of 3-[[5-chloro-2-[[[[2-(dimethylamino)ethyl]oxy]- -29- LV 12559 carbonyl]oxy]phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol- 2(3H)-one. mp 160-163°C; MS m/z 486 (MH+). 5 EKAMELE„3 2-rrrr4-Chloro-2-rr5-r4-(trifluoromethy0Dhenyl1-2.3-dihvdro-2-oxo-1.3.4-oxadiazol-3-ynmethvllphenoxv1carbonvlloxv1ethvn 10 trimethylammonium methanesulfonate

The crude 3-[[5-chloro-2-[[[[2-(dimethylamino)ethyl]oxy] carbonylļ oxy]phenyl]methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one was dissolved 1:1 ether-EtOAc and neat methyl methanesulfonate (2 eqt.) 15 was added. The mixture was stirred at room temperatūra ovemlght. The pracipitated solid was collected by filtration, washed with ether and then dried in vacuo to afford the title compound as a white soiid: mp 190-195°C (dec.); 20 IR (KBr, cm-1) 1193,1318,1765,1777; 1 H NMR (CDCl3) δ 2.76 (s, 3H), 3.51 (s, 9H), 4.19 (m, 2H), 4.75 (m, 2H), 4.89 (s, 2H), 7.17 (d, J = 8.6 Hz, 1H), 7.25 (s, 1H), 7.38 (dd, J = 8.6 and 25 2.5 Hz, 1H), 7.54 (d, J = 2.5 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H); MS m/z 500 (M+).

General procedūra for the preparation of Examoles 4-11 30 The follovving describes the general procedūra used for the preparation of compounds of the Formula Vlla-c and Vllla-c which is also -30- illustrated herein in Reaction Scheme 2. The acid chlorides of Formula Vla-c were prepared by reacting the corresponding acids with oxalyl chloride and a catalytic amount of DMF in CH2CI2. The acid chlorides of Formula Vla-c were isolated as HCI salt and used vvithout further 5 purification. To a stirred suspension of the compound of Example 1 (1 eqt.) and NaH (2 eqt.) in anhydrous ether, the corresponding acid chloride of Formula VI (1.2 eqt.) was added and the mixture was stirred for 3-4 hrs. The reaction mixture was diluted with ether and EtOAc, washed with 5% NaHC03, water, brine and then dried (MgS04). The solvents were 10 rotary evaporated and the residue was recrystallized from ether-hexanes to provide the compound of Formula Vlla-c. Neat methyl methanesulfonate was added to a solution of a compound of Formula Vlla-c in 1:1 ether-EtOAc and the mixture was stirred at room temperature ovemight. The precipitated white solid was filtered, vvashed 15 with ether and then dried in vacuo to afford the corresponding pure compound of Formula Vllla-c. EXAMPLE 4 20 4-Chloro-2-fr5-r4-ftrifluoromethvnphenvn-2.3-dihvdro-2-oxo-1.3.4-oxadiazol-3-vl1methvllDhenylfdimethvlamino1acetate (Vīla, n a 1) mp 112-113°C; MS m/z: 456 (MH+). C, 52.70; H, 3.76; N, 9.22. C, 52.51; H, 3.66; N.9.10. 25

Anal. Calcd. for C20H17CIF3N3O4:

Found: -31 - -31 - LV 12559 EXAMPLE 5 4-Chloro-2-rr5-r4-(trifluoromethvnphenvn-2.3-dihvdro-2-oxo-1.3.4-Qxadiazol-3-yt1methvnphenvl-3-(diethylamino)propionate (Vllb, n = 2) 5 mp 179-181 °C; MS m/z: 498 (MH+).

Anal. Calcd. for C23H23CIF3N3O4.HCI: C, 51.70; H, 4.53; N, 7.86.

Found: C, 51.46; H, 4.67; N, 7.71. 10 EXAMPLE 6 4-Chloro-2-Tr5-44-4trifluorofnethvnphenyl1-2.3-dihydro-2-oxo-1.3.4-oxadiazol-3-vllmethvnphenyl-4-(dimethvlamino1butvrate (Vīle, n = 3) 15 mp 162-164°C;

Anal. Calcd. for C22H21CIF3N3O4.HCI: C, 50.78; H, 4.26; N, 8.08.

Found: C, 49.51; H, 4.35; N, 7.80. 20 EXAMPLE 7 rrr4-Chloro-2-IT5-r4-(trifluoromethynphenvll-2.3-dihydro-2-oxo-1.3.4-oxadiazol-3-vl1methvllDhenoxvļcarbonyl1methyl1-25 trimethylammonium methanesulfonate (Villa, n = 1) mp 230-232Χ; MS m/z: 470 (M+).

Anal. Calcd. for C21H20CIF3N3O4.CH3SO3: C, 46.69; H, 4.10; N, 7.42.

Found: C, 46.06; H, 4.06; N, 7.21. 30 -32- EXAMPLE 8 2-rrr4-Chloro-2-rr5-r4-(trifluoromethvnphenvlļ-2.3-dihydro-2-oxo-1.3.4-Qxadiazol-3-vllmethvnDhenoxv1carbonvl1ethyl1-5 diethylmethvlammonium methanesulfonate (Vlllb, n = 2)

mp > 260°C EXAMPLE 9 10 3-rrr4-Chloro-2-rr5-r4-ftrifluoromethvnDhenvl1-2.3-dihvdro-2-oxo· 1.3.4-oxadiazol-3-yl1methvl1phenoxv1carbonyn-DroDvlltrimethvlammonium methanesulfonate (Vlllc, n = 3) 15 mp > 260°C; MS m/z: 498 (M+).

Anal. Calcd. for C23H24CIF3N304.CH3S03: C, 48.53; H, 4.58; N, 7.07.

Found: C, 48.61; H, 4.58; N, 7.03. 20 EXAMPLE 10 4-Chloro-2-iT5-r4-ftrifluoromethy0phenvl1-2.3-dihvdro-2-oxo-1.3.4- oxadiazol-3-vl1methvnphenvUmethvlamino1acetate 25 mp 186-188°C (dec.). EXAMPLE 11 4-Chloro-2-rr5-r4-/trifluoromethvQphenvn-2.3-dihvdro-2-oxo-1.3.4-30 oxadiazol-3-yHmethyrjphenyl-3-aminopropionate mp 184-185°C (dec.). -33- LV 12559 EXAMPLE 12 r4-Chloro2-rr5-f4-ltrifluoromethvnDhenvn-2.3-dihvdro-2-oxo-1-3.4-oxadia2ol-3-yl1methvnphenoxv1methvl-4-rdimethvlamino^būtvrate 5 (Xlc, n = 3)

Step A. 3-rr5-Chtoro-2-(methvlthiomethoxv^phenvnmethvn-5-r4-ftrifluoromethvnphenvn-1.3.4-oxadiazol-2f3H^one ΠΧ> 10 A solution of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4- (trifluoromethyl)phenyi]-1,3,4-oxadiazol-2(3H)-one (6.0 g, 16.2 mmol) in dry HMPA (50 mL) was added dropwise under nitrogen to a stirred suspension of sodium hydride (0.77 g of 60% dispersion in mineral oil, 19.4 mmol) in HMPA (15 mL). The resultant yellow solution was stirred 15 for 30 min and then neat chloromethyi methyl sulfide (1,49 mL, 17.8 mmol) was added dropvvise. The reaction mixture was stirred at room temperature ovemight and the product was extracted with ethyl acetate (500 mL). The EtOAc layer was vvashed with satd. NaHC03, water, brine and then dried (MgS04). Rotary evaporation of EtOAc gavē a yeilow 20 semi-solid which was recr/stallized from ethyl acetate/hexanes to afford the tītie compound as white crystals (4.4 g, 70%). 1H NMR (CDCI3) δ 2.28 (s, 3H), 5.00 (s, 2H), 5.22 (s, 2H), 6.92 (d, J = 8.5 Hz, 1H), 7.3 (m, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H). 25 IR (KBr, cm*1): 1779,1608,1494,1328,1238,1176,1126.

Anal. Calcd. for C18H14CIF3N203S: C, 50.18; H.3.28; N, 6.50.

Found: C, 50.19; H, 3.32; N, 6.52. 30 -34-

Step B. 3-rr5-Chloro-2-fchloromethoxvtohenvl]methvH-5-r4- ftrifluoromethvnphenvr)-1.3.4-oxadiazol-2i3/-A-one (X)

Neat sulfuryl chloride (0.78 mL, 9.75 mmol) was added dropwise to 5 a stirred solution of the compound from Step A (3.5 g, 8.12 mmol) in CH2CI2 (40 mL) under nitrogen. The reaction mixture was stirred at room temperature for 4 hrs. TLC indicated completion of the reaction. After removal of excess reaģent and CH2CI2 by rotary evaporation the product was dried under vacuum to afford the title compound as an off-white solid 10 (3.4 g, 100%). MS m/z: 419 (MH+). 1H NMR (CDCl3) δ 5.0 (s, 2H), 5,94 (s, 2H), 7.18 (d, J =* 9.2 Hz. 1H), 7.38 15 (m, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.96 (d, J =* 8.3 Hz, 2H). IR (KBr, cm*1): 1773,1611,1572,1487,1325,1163,1128. Aņai. Caicd. forC17H11CI2F3N2O3«0.25 H20: C, 48.19; H, 2.76; N, 6.61. 20 Found: C, 48.04; H, 2.68; N, 6.53.

Step C. r4-Chloro-2-IT5-f4-ftrifluoromethv0phenvn-2.3-dihvdro-2-oxo-1.3.4-oxadiazol-3-vnmethvnphenoxv1methvl-4-fdimethvlaminolbutvrate (Xlc, n = 3) 25

The chloromethoxy compound of Step B (0.8 g, 1.91 mmol) was added to a stirred suspension of Cs2C03 (1.306g, 4.01 mmol) and 4-(dimethylamino)butyric acid hydrochloride (0.352 g, 2.1 mmol) in acetone (20 mL). The reaction mixture was stirred at room temperature ovemight. 30 TLC indicated completion of the reaction. Acetone was rotary evaporated and brine solution was added. The yellow precipitate was collected by -35- -35- LV 12559 fiitration and vvashed with water and then air dried. The caide solid was recrystallized from ethyl acetate/hexanes to afford the tītie compound Xlc as a white solid (0.64g, 65%). 5 mp115-117°C; 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.02 (t, J * 7.0 Hz, 2H), 2.25 (t, J = 7.3 Hz, 2H), 3.32 (s, 6H), 4.92 (s, 2H), 5.79 (s, 2H), 7.24 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 2.6 Hz, 8.8 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 7.90 (d, J 10 = 8.5 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H). IR (KBr, cnr1): 1776,1764,1607,1492,1416,1324,1121.

Anal. Calcd. for Ο^Η^Ο^^Ο^Ο.δ HaO: C, 52.83; H, 4.63; N, 8.04. 15 Found: C, 53.00; H, 4.70; N, 8.04. BCAMPLE 13 3-rrrr4>Chloro-2-rr5-r4-(trifluoromethvnphenvn-2.3-dihvdro-2-oxo-20 1.3.4-oxadiazol-3-vllmethvllDhenoxv1methoxv1carbonyllDropyl] trimethvlammonium methanesulfonate (XIIc, n = 3)

The compound of Example 12 (Xlc) (0.95 g,1.85 mmol) was dissolved in ethyl acetate (10 mL) and neat methyl methanesulfonate 25 (0.32 mL, 3.7 mmol) was added dropvvise. The reaction mixture was stirred at room temperature ovemight. The white precipitate was collected and purified by trituration with ether to afford the title compound as a white solid (0.95 g, 82%). Recrystailization from ethanoi/ether gavē white crysta!s: mp 156-158°C; MS m/z: 528 (MH+). -36- 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.27 (s, 3H), 2.43 (t, J = 7.1 Hz, 2H), 3.01 (s, 9H), 3.22(m, 2H), 4.91 (s, 2H), 5.81 (s, 2H), 7.24 (d, J = 8.9 Hz, 1H), 7.43 (dd, J - 2.7 Hz, 8.8 Hz, 1H), 7.49 (d, J = 2.6 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H); 5

Anal. Calcd. for C24H2gCIFgN305*CHgS03; C, 48.12; H, 4.68; N, 6.73.

Found; C, 48.15; H, 4.74; N, 6.71. ΕΧΑΜΡΙΕ 14 10 rrrr4-Chloro-2-rr5-r4-/trifluoromethv0phenvn-2.3-dihvdro-2-oxo-1.3.4-oxadiazol-3-vl1methvllDhenoxvlmethoxv1carbonvl1methvl1 trimethvlammonium methanesulfonate (Xlla, n = 1) 15 Td a mixture of compound X from Example 12, Step B (0.4 g, 0.95 mmol), CS2CO3 (0.342 g, 1.05 mmol) and N,N-dimethylglycine (0.108 g, 1.05 mmol), acetone (20 mL) was added. The reaction mixture was stirred at room temperatūra ovemight. Acetone was rotary evaporated and then brine was added. The white precipitate of compound Xla (n = 1) was 20 collected and dissolved in acetonitrile and neat methyl methanesulfonate (0.053 mL) was added. The reaction mixture was stirred at room temperatūra for 2 days. The solvent was evaporated and ether was added. The precipitate was collected and purifīed by recrystallization from acetonitrile/ether to afford the tītie compound as a vvhite solid (0.13 g, 25 23% two steps), mp: 100-104°C. MS m/z: 500 (M+). 1H NMR (DMSO-dg) δ 2.27 (s, 3H), 3.33 (s, 9H), 4.60 (s, 2H), 5.09 (s, 2H), 5.48 (s, 2H), 7.24 (d, J=8.9 Hz, 1H), 7.52 (dd, J=2.6 Hz, 8.8 Hz, 1H), 7.60 (d, J=2.6 Hz, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.97 (d, J=8.3 Hz, 2H). 30 -37- LV 12559

Anal. Calcd. for CppH^iCIFaNaOs^CHaSOa* 1.5 H2O: C, 44.34; H, 4.53; N, 6.74.

Found: C, 44.35; H, 4.28; N, 6.46. 5 EXAMP.lg.15 r4-Chloro-2-rr5-r4-(trffluoromethvnDhenyn-2.3-dihvdro-2-oxo-1.3.4-oxadiazol-3-vl1methvl1phenoxvlmethvl-3“/dlethvlamino^Dropionate hvdrochloride (Xlb, n = 2) 10

To a mixture of compound X from Bcample 12, Step B, (0.4 g, 0.95 mmol), Cs2C03 (0.622 g, 1.91 mmol) and 3-(diethylamino)propionic acid hydrochloride (0.108 g, 1.05 mmol), acetone (20 mL) was added. The reaction mixture was stirred at room temperatūra for 3 days. Acetone was 15 rotary evaporated and brine was added to the residue. The precipitated vvhite solid (0.38 g, 75%) was collected. To a stirred solution of crude product (0.16 g, 0.30 mmol) in ethyl acetate 1N HCI in ether (0.36 mL, 0.36 mmol) was added and ķept at room temperature for 3 hr. The hydrochloride salt of the tītie compound Xlb was collected by filtration 20 (0.11 g, 64%): mp 165-167°C (dec.); MS m/z: 528 (MH+). 1H NMR (DMSO-dg) δ 1.16 (t, J=7.2 Hz, 6H), 2.93 (t, J=7.8 Hz, 2H), 3.01- 25 3.10 (m, 4H), 3.19-3.25 (m, 2H), 4.93 (s, 2H), 5.84 (s, 2H), 7.27 (d, J=8.8

Hz, 1H), 7.44 (dd, J=2.6 Hz, 8.8 Hz, 1H), 7.51 (d, J=2.6 Hz, 1H), 7.91 (d, J=8.5 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H), 10.5 (s, br, 1H).

Anal. Calcd. for Ca^ClFaNgCVHCI: C, 51.08; H, 4.64; N, 7.45. 30

Found: C, 46.94; H, 4.42; N, 6.76. -38- EXAMPLE 16 3-frrr4-Chloro-2-ff5-r4-ftrifluoromethvnDhenyl'ļ-2.3-dihvdro-2-oxo-1.3.4-Qxadia2ol-3-vllmethvllDhenoxvlmethoxvlcarbonvl1-2-5 hydroxypropyl1 trimethvlammonium methanesulfonate 0(111)

To a stirred suspension of compound X from Example 12, Step B (0.4 g, 0.95 mmol) and Cs2C03 (0.342 g, 1.05 mmol) in acetone (20 mL), (L)-norcamitine [Colucci, W.J.; Tumbull, Jr.f S.P.; Gandour, R.D.; 10 Analvtical Biochemistrv. 162, pp.459-462 (1987)] (0.155 g, 1.05 mmol) was added. The reaction mlxture was stirred at room temperature for 2 hr. Acetone was rotary evaporated and water was added and then extracted with ether. The extract was then vvashed with water, brine and dried (MgS04). Evaporation of ether gavē a yellowish foamy solid which was 15 then dissolved in ether and 0.1 mL of methyl methanesulfonate was added. The reaction mixture was stirred at room temperature ovemight. The precipitated solid was collected and triturated with ethyl acetate/ether to afford the title compound as an off-white solid (0.2 g, 33% two steps), mp: 98-101 °C. MS m/z: 544 (M+). 20 1H NMR (DMSO-d6) 52.30 (s, 3H), 2.52-2.58 (m, 2H), 3.10 (s, 9H), 3.34- 3.41 (m, 2H), 4.43 (m, 1H), 4.94 (s, 2H), 5.73 (d, J=6.2 Hz, 1H), 5.81 (d. J=5.5 Hz, 1H), 5.84 (d, J=6.6 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.44 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.99 25 (d, J=8.3 Hz, 2H); IR (KBr, cm-1): 3307,1784,1751,1490,1417,1324,1194,1123,1065.

Anal. Calcd. for C24H26CIF3N3O6eCH3SO3*0.75 H20: C, 45.95; H, 4.70; N, 6.43. Found: C, 45.88; H, 4.69; N, 6.13. 30 -39- LV 12559 BCAMPLE 17 2-rrrrr4-Chloro-2-rf5-f4-ftrifluQromethynphenvn-2.3-dihvdro-2-oxo-1.3,4-oxadia2ol-3-ynmethvriDhenoxvlmethoxvlcarbonvl1oxv1 5 ethvl1trimethylammonium methanesulfonate (XVHa. n = 11

Step A. 3-fi2-rrr(Butylthio^carbonvnoxvlmethoxv1-5-Chtoro-

Dhenvnmethvn-5-r4-ftrifluoromethvl^phenvn-1.3.4-oxadiazol- 2(3Hī-omOm 10

Sodium hydride (60% in mineral oil, 144 mg, 3.6 mmol) was added to stirred cold (0°C) solution of the compound of Formula II (1.11 g, 3 mmol) in dry HMPA (6 mL) under nitrogen and then allowed to warm to room temperature. After 30 min. the resultant yellow solution was cooled 15 to 0°C and then neat 0-iodomethyl-S-butyl carbonothioate [Folkman, M. and Lund, F., Svnthesis. pp.1159, (1990)] (1.0 g, 3.6 mmol) was added dropvvise. The resultant mixture was allovved to warm to room temperature and stirred ovemight. Saturated brine was added to the reaction mixture and the precipitated vvhite solid was filtered, washed 20 thoroughly with water. The crude wet solid was dissolved in 1:1:1 EtOAc-CH2CI2-THF and then dried (MgSO^. Filtration and evaporation of solvents gavē a vvhite solid (1.76 g) vvhich was recrystallized from ether to afford pure XIV (693 mg, 62%). 25 Step B. r4-Chloro-2-ff5-r4-(trifiuoromethvibhenvn-2.3-dihvdro-2-oxo-1 3.4-oxadiazol-3-vnmethvnphenoxv1methvl chloroformate m

Neat sulfuryl chioride (80 μί, 1 mmol) was added to a stirred 30 solution of the compound of Step A (258 mg, 0.5 mmol) in anhydrous CH2CI2 (2 mL) under nitrogen. The resultant mixture was stirred at room temperature for 2 hrs. The reaction mixture was rotary evaporated to -40- dryness at room temperature and then ķept under high vacuum to afford the desired chloroformate of Formula XV as a vvhite soiid (0.23 g).

Step C. 3-rr5-Chloro-2-rrfff2-fdimethvlamino1ethyl]oxyl 5 carbonvrļoxv1methoxvlDhenyflmethvn-S-f4-itrifluoromethvn- phenvn-1.3.4-oxadiazol-2f3H)-one (XVIa, n = 1)

Neat dry 2-(dimethylamino)ethanol (134 mg) was added to a stirred solution of the compound of Formula XV from Step B (0.23 g) in 10 anhydrous CH2CI2 (5 mL) and the mixture stirred ovemight. Reaction mixture was diluted with CH2CI2 and then quenched with 5% NaHC03< Organic layer was separated and washed wrth water, brine and then dried (MgS04). Evaporation of CH2CI2 gavē the title compound as a light yellow oil (0.21 g). 15

Step D. 2-fīfff4-Chloro-2-IT5-r4-ftrifluoromethvnphenvn-2.3-dihvdro-2- 0x0-1 3.4-oxadia2ol-3-vl1methvnphenoxvlmethoxv1-carbonvr|oxvļ ethvfltrimethylammonium methanesulfonate (XVIIa, n = 1) 20

The crude product from Step C (0.2 g) was dissolved in 1:1 ether-EtOAc (5 mL) and treated with methyl methanesulfonate (2 eqt.). The mixture was stirred at room temperature ovemight and the precipitated vvhite soiid was filtered, vvashed with ether and then dried in vacuo to 25 afford the title compound as a vvhite soiid (94 mg): mp 145-150°C (dec.); 1H NMR (CDCI3) δ 2.76 (s, 3H), 3.45 (s, 9H), 4.16 (m, 2H), 4.71 (m, 2H), 4.96 (s, 2H), 5.79 (s, 2H), 6.98 (d, J = 8.4 H2, 1H), 7.31-7.34 (m, 2H), 7.75 (d, J * 8.4 Hz, 2H), 7.97 (d, J = 8.2 Hz, 2H); MS m/z 530 (M+). 30 -41 - Claim LV 12559 1. A compound of the formula

5 vvherein A B D 10 n R is a direct bond or -CH20-; is a direct bond or oxygen; is -(CH2)n- or -CH^HOHCH2-; is an integer from 1 to 4; Θ Θ Θ is —NR1R2 or —NR1R2R3X in vvhich X is a counter anion; and R1, R2. and R3 each are independently hydrogen or alkyl; 15 or a nontoxic pharmaceutically acceptable salt or solvate thereof. 2. The compound of claim 1 vvherein A is a direct bond, B is a direct bond, and Dis -(CH^n*· 20 3. The compound of claim 2 selected from the group consisting of: 4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl]methyl]phenyl(dimethylamino)acetate; 25 4-chloro-2-[(5-[4-(trifIuoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl]methyl]phenyl-3-(diethylamino)propionate; -42- 4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4- oxadia2ol-3-yl]methyl]phenyl-4-(dimethylamino)butyrate; [[[4-chloro-2-[[5-[4-(trifiuoromethyl)phenyl]-2,3-dihydro-2-oxo-1l3,4-5 oxadiazol-3-yl]methyl]phenoxy3carbonyl]methyl]trimethylammonium methanesulfonate; 2- [[{4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3I4-oxadiazol-3-yl]methyl]phenoxy]carbonyl]ethyl]diethylmethylammonium 10 methanesulfonate; 3*H4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2l3-dihydro-2-oxo-1,3,4- oxadiazol-3-y!]methyl]phenoxy]carbonyl]propyl]trimethylammonium methanesulfonate; 15 4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl]methyl]phenyl(methylamino)acetate; and 4-chloro-2-[[5-[4-(trifluoromethyl)phenyl3-2,3-dihydro-2-oxo-1,3,4-20 oxadiazol-3-yI]methyl]phenyl-3-aminopropionate; or a nontoxic pharmaceutically acceptable salt, counter anion or solvate thereof. 25 4. The compound of clalm 1 vvherein A is a direct bond, B Is oxygen andDis -(CH^n*· 5. The compound of claim 4 selected from the group consisting of: 3- [[5-chloro-2-[[[[2-(dimethylamino)ethyl]oxy] carbonylļoxy]phenyI]methyl]-30 5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one; and -43- -43- LV 12569 2- [[[[4-chloro-2*[[5-[4-(trifluoromethyl)phenyi]-2,3-dihydro-2-oxo-1f3,4-oxadiazol-3*yl]methylļphenoxy]carbonyl]oxylethylltrimethylammonium methanesulfonate; 5 or a nontoxic pharmaceutically acceptable salt, counter anion or solvate thereof. 6. The compound of daim 1 wherein A is -CH20-, B is a direct bond and D is -(CH^n·. 10 7. The compound of claim 6 selected from the group consisting of [4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yQmethy0phenoxy]methyl-4-(dimethylamino)butyrate; 15 3- [[[[4-chloro-2-[[5-[4-(trrfluoromethyi)phenyi]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl]methyl]phenoxy]methoxy]carbonyl]propyl] trimethylammonium methanesulfonate; 20 [[[[4-chloro-2-{I5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yI]methyl]phenoxy]methoxy]carbonyl]methyl] trimethyiammonium methanesulfonate; and [4-chloro-2-fl5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-25 oxadiazol-3-yl]methyI]phenoxy]methyl-3-(diethylamino)propionate hydrochloride; or a nontoxic pharmaceutically acceptable salt, counter anion or solvate thereof. 30 -44- 8. The compound of claim 7 which is 3-[[[[4-chloro-2-[[5-[4-(trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1l3,4-oxadiazol-3-yl]methyl]phenoxy]methoxy]carbonyl]propyl]trimethylammonium methanesulfonate. 5 9. The compound of claim 1 vvherein A is -CH20-, B is a direct bond and D is -CH2CHOHCH2-. 10. The compound of claim 9 which is 3-[[[[4-ch!oro-2-[[5-[4-10 (trifluoromethyl)phenyl]-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3- yl]methyl]phenoxy]methoxy3carbonyl]-2-hydroxypropyl3 trimethylammonium methanesulfonate. 11. The compound of claim 1 vvherein A is -CH20-, B is oxygen, and D 15 is -(CH^n-. 12. The compound of claim 11 vvhich is 2-fTTfī4-chloro-2-fi5-f4-(trifluoromethyl)phenyl3-2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl3methyl3phenoxy3methoxylcarbonyl3oxylethyl3trimethylammonium 20 methanesulfonate. 13. A pharmaceutical composition for the treatment of disorders responsive to openers of the large conductance calcium-activated potassium channels comprising a therapeutica!!y effective amount of a 25 compound as defined in claim 1 in association with a pharmaceuticaily acceptabie carrier or diluent. 14. A method for the treatment of disorders responsive to opening of the large conductance calcium-activated potassium channels in a 30 mammai in need thereof, vvhich comprises administering to said mammai a therapeutically effective amount of a compound as defined in claim 1. LV 12559 -45- 15. The method of claim 14 vvherein said disorder is ischemia, stroke, convulsions, epilepsy, asthma, irritable bowel syndrome, migraine, traumatic brain injury, spinal cord injury, sexual dysfunction and urinary incontinence. 5 16. The method of claim 15 vvherein the disorder is stroke. -46- -46- LV 12559

ABSTBACT

The present invention provides novel oxadiazolone derivatives 5 having the general formula

vvherein A, B, D and R are as defined herein, or a nontoxic 10 pharmaceutical!y acceptable salt or solvate thereof and are usefui in the treatment of disorders which are responsive to the opening of the large conductance calcium-activated potassium channels.

Claims (15)

Formula 1. A compound of formula (I) wherein: A is a bond or a group -CH 2 O-; B is a bond or an oxygen atom; D is - (CH 2) n - or -CH 2 CHOHCH 2 -; n is an integer from 1 to 4; R is -NR1R2 or -N®R1R2R1X " where X * is an counter-ion; R 1, R 2 and R 1, independently of one another, are hydrogen or C 1-4 alkyl, or a non-toxic pharmaceutically acceptable salt or solvate thereof. The compound of claim 1, wherein: A is a bond, B is a bond, and D is- (CH2) n-. 1 Compound of Claim 2, taken from the group: dimethylaminoacetic acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl ] methyl} phenyl ester; 3- (diethylamino) propionic acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenyl ester; 4- (dimethylamino) butyric acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenyl ester; 4-Chloro-2- {15- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl] phenol trimethylammonioacetic acid ester methanesulfonate; 4-Chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenol 3- (diethylmethylammonio) propionic acid ester methanesulfonate ; 4-Chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl] phenol 4- (trimethylammonio) butyric acid ester methanesulfonate; methylaminoacetic acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-113,4-oxadlazol-3-yl] methyl} phenyl ester; 3-Aminopropionic acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenyl ester or a non-toxic pharmaceutically acceptable salt thereof; internal salt or solvate. The compound of claim 1 wherein: A is a bond, B is an oxygen atom, and D is - (CH 2) n -. 5. A compound according to claim 4 selected from the group consisting of: 3- {5-chloro- [2- (2-dimethylaminoethoxy) carbonyloxy] phenylmethyl} -5- (4-trifluoromethylphenyl) -1,3,4-oxadiazole -2 (3H) ons; 4-Chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3-oxadiazol-3-yl] methyl} phenol and 3- (trimethylammonio) propanol carbonic acid methanesulfonate ; or a pharmaceutically acceptable salt, quaternary salt or solvate thereof. The compound of claim 1, wherein: A is -CH2O-, B is a bond, and D is- (CH2) n-. 7. The compound of claim 6, taken from the group: 4- (dimethylamino) butyric acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4 -oxadiazol-3-yl] methyl} phenoxymethyl ester; 4-Chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenoxymethanol 4- (trimethylammonio) butyric acid ester methanesulfonate; EN 12559 trimethylammonioacetic acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenoxymethanol ester methanesulfonate; 3- (diethylamino) propionic acid 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl} phenoxymethyl ester hydrochloride; or a non-toxic pharmaceutically acceptable salt, quaternary salt or solvate of the ST compound. 8. The compound of claim 7, namely, 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,3-oxadiazol-3-yl] methyl] phenoxymethanol 4- (trimethylammonium) butyric acid methane sulfonate. The compound of claim 1, wherein: A is -CH 2 O-, B is a bond and D is -CH 2 CHOHCH 2 -. 10. The compound of claim 9, namely, 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methyl. } Phenoxymethanol 4- (trimethylammonio) -2-hydroxy-acetic acid ester methanesulfonate. The compound of claim 1, wherein: A is -CH 2 O-, B is oxygen and D is - (CH 2) n -. 12. The compound of claim 11, namely, 4-chloro-2 - {[5- (4-trifluoromethylphenyl) -2,3-dihydro-2-oxo-1,3,4-oxadiazol-3-yl] methylphenoxymethanol and 2- (trimethylammonio) ethanol carbonic ester methane sulfonate. 13. A pharmaceutical composition for the treatment of diseases which are treatable with substances that open up calcium ion-activated high permeability potassium channels, comprising a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier or diluent. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment of diseases which are treatable with substances that open the calcium ion-activated high permeability potassium channels. Use according to claim 14, wherein said diseases are ischemia, stroke, seizures, epilepsy, asthma, irritable bowel symptom, migraine, brain injury, spinal cord injury, sexual dysfunction and urinary incontinence. 16. The use of claim 15 wherein the disease is stroke.